Today, the questions are focused on some very critical issues for the Cell Surgical Network including potential FDA regulatory factors for the Network, the definition of their SVF product (biological drug or not a drug), and whether homologous use (see more on homologous use here) applies to their clinical interventions. In addition, I questioned them about why patients have to pay to be part of the Network clinical trial. I also asked for their vision of the future.

1. There seem to be some divergent views on SVF. On occasion the FDA has indicated that in certain circumstances that SVF is a 351 biological drug not strictly regulated by 361 HCT/P regs, but it seems this is on a case by case basis. On the Cell Surgical Network websites it is stated unambiguously that the Network clinics do not need FDA approval for use of SVF. Why do you hold that view? Have you received guidance from the FDA that your SVF product is not a drug? Have you met with the FDA to talk about these kind of issues and if so, how’d that go?

Lander/Berman: I asked Dr. Berman to weigh in on this and here are some of his comments…It seems everyone seems to ignore or forget the PURPOSE of 21 CFR part 1271 – namely to prevent the transmission of communicable disease. The only reason the FDA can claim that HCT/Ps are a drug is if they are being processed in a laboratory manner or have the potential of transmitting communicable disease. Once you use a laboratory to process the cells you are under FDA jurisdiction and they have a list of validation procedures they require all facilities to meet. It’s rare that a physician with a laminar flow hood or a laboratory actually meets these validation standards. If they don’t meet these standards, then the FDA asserts that there is risk of disease transmission and as such claims authority and requires an IND.

California Stem Cell Treatment Center and all members of the Network use a completely closed sterile surgical procedure to isolate SVF (not pure stem cells). There is no laboratory processing of the cells. All supplies, devices and drugs are already FDA approved though not specifically for SVF / stem cell production. As is typical of many surgical devices and drugs, it is completely legal, ethical and appropriate to use approved products “off-label.” While we have followed the FDA exemptions listed in part 1271, we are not really under the FDA jurisdiction as they have NO jurisdiction or ability to approve surgical procedures – just devices and drugs. Since we do not use a laboratory method to produce SVF, only a surgical method, then there is nothing for the FDA to validate in our process. There is simply no risk of transmission of communicable disease. Arguably, Ceteno (sic), Celltex, Intellicell and others all have laboratory involvement that didn’t meet FDA standards for GMP production of HCT/Ps. The FDA mandates are based on the Congressional desire to prevent organ donors from transmitting disease – so it isn’t a question of mass numbers (as one sees with most drug productions), just a question of validating one’s laboratory procedures.

We produce SVF (over 40 ingredients and can’t be characterized) in a surgical procedure (can’t be approved by the FDA – they’ve never approved a surgical procedure). If the FDA can’t approve a surgical procedure, why would we possibly request them to approve this procedure? Also, since the FDA is concerned that they could be responsible for any drug they approve, it’s unlikely they would approve anyone by written request as it would leave them liable without having done their “due diligence.”

Finally, the FDA has audited our IRB approved protocol and there was never any communication indicating that it wasn’t appropriate. Out of the 29 protocols from the ICMS IRB reviewed, only one was rejected by the FDA (not ours). That, in itself, is an indication that we are not in any violation of FDA regulations.

2. Your website & clinical trial page indicate that the Network treats perhaps as many as a few dozen different conditions with SVF (http://www.stemcellrevolution.com/currently-studying/). What is the evidence to support such diverse, seemingly in many cases non-homologous use of SVF?

Lander: We do have many conditions that we are looking at and in choosing them we have attempted to exploit either the regenerative, immuno-modulatory, or anti-inflammatory properties of SVF. Although SVF is used in all of our protocols, our deployment techniques vary considerably. I think the term homologous has been used rather loosely and in the field of regenerative medicine, a new paradigm defies simplistic categorizations of cell types. After all, what type of tissue is an undifferentiated progenitor cell? Can it be homologous? Isn’t it potentially everything? For example, if it forms cartilage then could it have ever been anything other than a cartilage precursor? Our comfort zone is that we are surgeons performing a type of surgical tissue transfer procedure. There is no difference than when we replace a bladder with ileum or a coronary artery with a saphenous vein from an extremity. At the end of the day, the ability to use various tissues to treat human disease is within the realm of a surgeon’s domain.

3. In terms of mechanism, how do you believe the SVF therapy works to help patients with specific conditions? Is the mechanism more of a “cell therapy” approach where the cells engraft and help heal a tissue or is it more of a trophic/growth factor mechanism where SVF stimulates existing tissue and cells to become healthier? Both? Depends on the condition?

Lander: Our SVF is essentially uncharacterized but we do know that it contains a rich broth of cells and growth factors. Although there may be conditions of engraftment and transdifferentiation of cells, the autocrine and paracrine effects of the growth factors play a major role in the healing effects we are seeing. This may explain, for example, why it is possible to treat neurologic diseases by mitigating nerve damage using cells that may not easily form nerve tissue.

Lander: Our project relies on patient funded research. We are very transparent about the fact that we are a research organization but also a business entity. Treatments are generally 6 to 9 thousand dollars but that can vary. We set fair prices back when we started in 2010 and thereby provided an alternative for patients who at that time were going overseas and paying 30-90 thousand dollars for nebulous treatments. Most government grants mandate that we apply for an IND investigational new drug application with the FDA. Pharmaceutical companies may not perceive value in our research because it is hard to monetize and commercialize autologous cells. Charitable sources are difficult to obtain and so we have turned to our patients. This is a reasonable approach yet we are always reminded that our consent process for paid investigational procedures must be very specific and comprehensive.

5. How did you first get interested in stem cells and what excites you the most about stem cells looking to the future?

Lander: The serendipitous identification of large numbers of readily accessible adult mesenchymal cells in fat has offered a unique opportunity for physicians to help their patients treat disease. Physicians take the Hippocratic Oath which mandates that we must do everything in our power that is safe to help our patients. Clinicians need to collaborate closer with basic science researchers to move the translational ball along farther. Our safety data is excellent so far. We hope to provide placebo controlled trials using cryo-preservation of SVF in the near future. Physicians from different specialties will be bringing their expertise to our organization and we are watching our database grow. The future has so much potential as we learn to define which cell types, deployment methods, and combination of growth factors work best for specific diseases enabling us to distinguish optimal treatments.

First of all I have use the Medikan system in the past and it is far from being a closed system and second one must use collaganese with it to make SVF and an shaking incubator. This clearly is not a surgical procedure and it is clearly a lab procedure and the system is not FDA approved to make SVFC. Also the fact the patients are paying for the procedure is clearly in violation of the FDA laws and the study is registered as a safety study and the other offices are not listed. I am worried for the doctors involved who may be risking their medical license and careers. The PHS 361 CFR 1271.10 (a) and CFR 1271.15 (b) are very clear in their requirements and the Medikahn system violates this. I and many other physicians have received letters from the FDA via the use of collaganese and that it is 351 ie is drug. I would love to see a legal opinion from the FDA lawyers involved with the Cell Surgical Network group. I would be more than happy to share my FDA letter re Collaganese if you want.

I have had communications with the FDA about CFR 1271.15 (b) and they point to the wording of “Such cells” and they believe if you use collaganese the cells are not the same as those taken out and those put back in so they are in violation of 1271.15 (b) and we at Intellicell have shown the FDA by using just a mechanical separation (ultrasonic cavitation) that the sames taken out are the same as those put back in.

Steven,
1271.10 defines HCT/P minimal manipulation, not 1271.15.
1271.15 covers exceptions from 1271.10, one of which says – you don’t need to comply with 1271.10 if it’s done within “same surgical procedure”.

As I said earlier, the biggest issue is using device for the purposes, which is not indicated. It’s illegal. When FDA approves device, it approves it for particular indications. Therefore, the use of MediKhan device in neurology is illegal.

All, Dr. Berman has been told by at least one medical conference by a regulatory attorney (Andy Ilttleman, Esq.) that his interpretation of the 1271.15b same surgical procedure exemption is not correct. In addition, there are at least two letters (one we received after we pinged the TRG and the Rodriguez letter) that ask if SVF processed during the same surgical procedure by the physician for use in joints and cosmetic procedures is the practice of medicine. Both letters clearly state that even in these circumstances, the SVF is a 351 biologic drug that needs approval. Hence there is nothing out of FDA that support’s Dr. Berman’s conclusion and he has already been warned by a very experienced regulatory attorney. The layering of an IRB approval and claim of a study only increases, not decreases the regulatory risk. This is because the SVF is a drug, hence Dr. Berman’s operation will be viewed as a drug manufacturer (like Pfizer) and as such, the study will be viewed as a drug study. The FDA “review” of his study through their audit of the ICMS IRB is being misrepresented. The ICMS IRB was warned by the FDA that SVF studies would be viewed as drug studies and the IRB didn’t have an FWA that would be needed for such studies and that their continued approval of such studies could lead to further regulatory action. In addition, calling this a study only increases the regulatory requirements that a physician’s office won’t meet.
Similarly, the use of a device created to make SVF again increases Dr. Berman’s risk and again doesn’t decrease it. This is because the kit is mislabeled and it’s import for use to create SVF may violate US import/export laws. In addition, I know from FDA’s writings in our case that the FDA views the practice of medicine as the use of FDA approved drugs and devices “off-label”. So without an FDA approval for this device, FDA’s view will be that the use of the device can’t be the practice of medicine (as they define it). In summary, I think Dr. Berman is misinterpreting FDA’s inaction as “approval” and not what it it really represents, i.e. “we just haven’t’ gotten to you yet…”

On the other side of this coin, as a physician, I agree that SVF isn’t a drug and that whatever a physician produces/uses on an individual patient is by definition POM, whether that item is FDA approved or not. My views above represent what FDA has put in writing. I strongly disagree with FDA’s positions on this issue, but at the same time, recognize that this is their view and that they intend to enforce these views until told otherwise by the judicial system.

Alexey, the legal experts on this who have read and digested all of the existing written documentation out of FDA state that the FDA is interpreting these such that the manipulation portion of the regs modify the other parts. In this case, if the processing of the SVF exceeds minimal manipulation, then the 1271.15(b) exemption can’t be used. So for example, I think at face value, we’d all agree that if a doctor were to transfect a new gene into stem cells with a viral vector, it wouldn’t matter than the transfection happened at the bedside, the “product” would be > min manip and hence FDA would consider it a drug. As I’ve stated, they have made this clear, as both our letter here (https://app.box.com/s/v8du7czi944s3xlblr5g) and the Rodriguez letter here (http://www.cosmeticsurg.net/blog/2012/01/11/fda-stem-cells-from-your-own-fat-are-a-drug/) were posed to the FDA Tissue Reference Group with the doctor processing the cells at the bedside. They both came back that it was the mere act of breaking down the structural tissue that created the “drug event”. In addition, there was only ever one guideline on the 1271.15(b) exemption published, but FDA pulled it about a year ago. In that Guidance for Industry (now pulled from their web-site), FDA made it clear that it was referring only to FDA approved devices for processing cells (510K cleared).

Dr. Berman invited Andy Ittleman to speak at one of his conferences on stem cells. I spoke to him after the conference Andy told the doctors that their processing of SVF would be considered a drug based on what FDA had put in writing. I would ask Dr. Berman why he is ignoring these warnings from regulatory counsel.

Chris,
Are you saying that FDA does not contradict itself when call SVF for 351 pathway, despite exceptions outlined in 1271.15? And do you think it’s because we (or me) misunderstand the term “same surgical procedure”? Correct? Do you think FDA is crystal clear?
What is the FDA’s definition of “same surgical procedure” then? So, once your took cells out of body and input into device isn’t it the “same surgical procedure” any more?

Why would Lander and Berman do this? To me it’s quite obvious. They have between 18,000,000 and 27,000,000 million reasons to ignore legal counsel. ($6000-9000 X 3000) They’ve apparently already hit the $6,000,000 – $9,000,000 mark after treating 1,000 patients in their “clinical trial”. The worst thing that could possibly happen is that “maybe” they get a letter from the FDA that says “Pretty please, won’t you stop treating patients with SVF? You can keep your medical licenses and you can keep all the money but you can’t keep doing this or you might make us angry and get yourselves into real trouble.” Of course, that’s IF (note the “big” IF) they every get a warning letter at all, which so far they haven’t. This whole thing is a complete farce. Interesting to me that an ICMS IRB would ever agree to oversee such a “trial” in the first place. But hey, if I am a bald, muscular dystrophy patient with erectile dysfunction and poor vision, one shot of my own fat cells migh just be the ticket!

It would be interesting for someone who is really “in the know” to give a breakdown of the actual costs. I note that Cell Surgical Network is claiming to be an order of magnitude less expensive than offshore clinics…

I’m not assuming anything. That’s a simple revenue calculation based upon the number of patients they claim to have treated so far and amount of money they say they charge them. Their information on clinicaltrials.gov says they are going to treat 3000 patients in the next year and a half or so. It probably costs them several hundred dollars to process a small fat sample in that machine plus their cost of performing a very quick and easy (non-aesthetic) liposuction. My best guess is that they are making a handsome profit with gross margin of 40-75%. Of course, there’s nothing wrong with making money but there might be something wrong with treating genetic diseases like muscular dystrophy with a single shot of autologous SVF…

OK, so let’s end the fantasy that SVF processed during the same surgical procedure is considered by FDA to be the practice of medicine. I called Andy Ittleman (who tried the Cytori SVF device case in the DC Circuit) and he sent me his slides from Dr. Berman’s stem cell cosmetics workshop. See https://app.box.com/s/qlabkguphwhbrlih5m6v. Take a look at slide 21 (Title is “Same Surgical Procedure”), which is derived from the administrative record for 1271. For those of you who don’t know, an administrative record is kept for all new regs promulgated by FDA or any government agency. Slide 21 clearly states that time is not the driving factor in the decision on whether a biologic is a 351 drug. The processing is the driving factor, in this case any attempt to breakdown the structure of the fat to SVF is beyond minimal manipulation. Also see the reference to the FDA TRG web-site for a doctor using SVF during the same surgical procedure to treat urinary incontinence (listed on the CSN web-site as a therapy). See http://www.fda.gov/biologicsbloodvaccines/tissuetissueproducts/regulationoftissues/ucm152857.htm . About the middle of the page under the FY 2008 updates:

“Autologous adipose tissue enzyme digested and processed for urinary incontinence and treatment of impotence is considered a biological product and not a 361 HCT/P because this is a non-homologous use. The tissue is recovered during one surgical procedure, then processed, and therefore the HCT/P is not exempt from the regulations under 21 CFR Part 1271.15(b).”

I’m not sure that FDA could make it clearer here. They state here that the non-homologous use trumps the 1271.15(b) physician exemption. This also means that the SVF Dr. Berman is offering patients to treat urinary incontinence is considered by FDA in writing to be a drug.

In the end, it’s very concerning that we have companies like CSN and notably Ageless who are routinely telling physicians that the same surgical procedure exemption allows them to process SVF for their own personal use. Both of these principles (Berman and Comella) have been at numerous conferences where legal experts have specifically pointed to what FDA has written to show that FDA believes that processing of SVF is a drug, regardless of whether you process it during the same surgical procedure or not.

Again, I don’t agree with FDA’s position nor do I believe they have a legal leg to stand on when trying to apply drug regulations to a doctor’s offices. However, telling doctors that FDA believes that SVF processed in their offices is exempt from drug regulations is dishonest and wrong.

While I don’t agree with the way the FDA regulates autologous stem cell therapies, I do have some concerns about Cell Surgical Network. I speak not as a physician nor as a stem cell scientist — only from the point of view of an ordinary guy, a trying-not-to-be-a-totally-dumb patient, if you will.

First, I get real concerned when I see a long list of diseases being treated based upon one underpinning method. It raises red flags. So, I just selected one disease (knee arthritis) and checked out the “physician network map”. Of course, the map did not identify which physicians were relevant to the disease. So I opened each CV and searched for “arthritis”. I only got one hit. A bit thin on the ground, I thought.

Looking at the CV’s, it was clear that a small minority were published in the scientific literature. That’s not a fatal flaw. One does not expect all doctors to publish. And if one disease was being treated by a team of 50 doctors and a bunch of academic researchers then I would not care if only a minority of the doctors published. But here we have seem to have far more diseases than published expertise…

This made me wonder, “what is the value/purpose of this data set?” given that the team and diseases are manifold and disparate. Indeed, it was not even clear to me that the data set would be used for publishing in the open literature — perhaps only for in house sharing?

Second, I carefully read:http://www.stemcellrevolution.com/currently-studying/orthopedics/knee-problems/
I was bothered that there were no references to published studies that might back up the treatment.
I was bothered by statements like “There are several alternatives to knee surgery such as injection of cartilage substitutes or steroids.” Really, I’ve not come across injectable cartilage substitutes. Hyaluronan perhaps? But that certainly isn’t a substitute for cartilage. And to suggest that substitutes exist sounds simplistic even to a simple-minded fellow like me!

I will not go on any further — although I certainly could do so — except to say that I actually think that the unreasonable attitude of FDA (and some others) are actually part of the problem. If the FDA was more pragmatic it would be more likely that teams of physicians (+scientists) with comprehensive expertise for specific diseases might actually form and and utilize published cell science in order to do useful work! Unfortunately, the FDA prescribes that only the Big Pharma model can be used for cell therapies (cells=drugs) — so that leaves everyone else in “work-around mode”.

I thought we beat this to death in the 1980s when we routinely implanted uncemented joints that were clearly labeled “only for use with bone cement” including hydroxyl apatite.
There is widespread use of Platlet Rich Plasma which is processed similarly to SVF (harvest-anticoagulation-centrifugation-reversal of anticoagulation- distant application) but the package has no cautions or restrictions.